Cyclosporin A Upmodulates Bleomycin-Induced Pulmonary Fibrosis in BALB/c Mice

Abstract

Background: Intratracheal instillation of bleomycin (Bleo) into rodents serves as a model for human lung fibrosis. Various mouse strains respond differently to Bleo, and BALB/c mice are relatively resistant. Objective: Since T lymphocytes have been shown to play a major role in this model, the effect of the immunomodulator cyclosporin A (CyA) on lung fibrosis was studied in Bleo-‘resistant’ BALB/c mice. Methods: Pulmonary fibrosis was induced by a single intratracheal (IT) instillation of Bleo. One of the four following treatments was given to one of four groups of female BALB/c mice: (1) Bleo-CyA: IT Bleo and daily intraperitoneal (IP) injections of CyA 100 mg/day starting 1 day before IT instillation of Bleo; (2) Bleo-Sal: IT Bleo and IP injections of saline; (3) Sal-CyA: IT saline and IP CyA 100 mg/kg; (4) Sal-Sal: IT and IP saline. The animals were killed on day 14. Fibrosis was evaluated by analysis of hydroxyproline and by quantitative image analysis of the fibrosis fraction. Ex vivo IFN-γ, IL-4, IL-13 and IL-5 secretion by peribronchial lymphatic tissue lymphocytes was measured. Results: Pretreatment with CyA upmodulated Bleo-induced lung fibrosis in the Bleo-‘resistant’ BALB/c mice; hydroxyproline was higher in Bleo-CyA compared to Bleo-Sal animals and both hydroxyproline and fibrosis fraction measurements were higher in Bleo-CyA compared to Sal-Sal. Cytokine secretion by lymphocytes demonstrated increased IFN-γ/IL-4 and IFN-γ/IL-13 mean secretion ratios in the Bleo-CyA animals compared to the Bleo-Sal animals. Conclusions: These results indicate that CyA upmodulates Bleo-induced lung fibrosis in Bleo-‘resistant’ BALB/c mice by allowing the emergence of a Th1 inflammatory response.